Several indirect lines of evidence suggest that the resorption of bone that accompanies aging can entail the heightened release of lead that, over decades, had accumulated in bone. moreover, indirect evidence suggests that this release of bone lead stores into the circulating pool of lead may contribute to adverse cognitive effects that accompany aging. Without an in vivo measure of bone lead stores, however, it has not been possible to test these hypotheses directly in epidemiologic studies. We propose to upgrade and use out state-of-the-art k-x-ray (K-XRF) fluorescence instrument located at the Clinical Research Center of the Brigham and Women's Hospital to make prospective measurements of bone lead levels in the men and women who participate in the normative Aging and the nurses Health Studies, respectively. We have already demonstrated in preliminary work using our prototype K-XRF instrument that a) trabecular bone lead levels are correlated with blood lead levels, with increasing steepness of the relationship with aging; (b) women who had fewer pregnancies have higher bone leads; and (c) some measures of cognitive performance are cross-sectionally related to bone and blood lead. For both men and women during the life of this project, we will be able to collect at least a second and third observation of data, including bone lead, blood lead, dietary assessments, and urinary measures ob bone turnover. We will also add a one-hour battery of neuropsychological tests to our regular evaluations in order to assess cognitive functioning. Designated subjects with either high or low bone lead values will have intensive home assessments for environmental lead exposure. We will over-sample women in the Nurses Health Study aged 49-53 in order to capture those at greatest risk of entering menopause. Our major statistical analyses will focus on (1) the relative contributions of bone lead vs. environmental lead exposure to blood lead and change in blood lead over time, and the modifying effect of age-associated bone turnover, and (2) bone lead as a predictor of performance on neuropsychological testing. In addition, we will examine secondary hypotheses regarding the modifying influences of dietary calcium and polymorphism of the ALA-D gene on these relationships.